This study aimed to analyze the safety and mid-term outcomes of a hybrid treatment method combining rotational atherectomy (RA) with drug-coated balloon (DCB) angioplasty in patients with femoropopliteal artery in-stent restenosis (ISR).This single-center retrospective study enrolled patients from January 2018 to March 2022 who had femoropopliteal artery in-stent restenosis treated by RA and DCB. Preoperative demographics, operative details, and postoperative 12-month follow-up outcomes were analyzed statistically.38 consecutive patients (31 men; mean age 69.55 ± 9.18 years, range 54-91 years) with Tosaka II (n = 8) and III (n = 30) ISR were treated with RA Most patients had a high prevalence of typical vascular comorbidities. Overall, 50% of patients had chronic limb-threatening ischemia, and the average lesion length was 155.0 ± 54.8 mm. The primary patency rate, assessed by duplex ultrasound at 12 months, was 86.7%; 7.9% (3/38) of patients underwent target lesion revascularization (TLR). The overall mortality rate was 2.6% (1/38), and the ulcer healing rate reached 83.3% (5/6), with none of these patients requiring amputation. Subgroup analysis based on target lesion length (≥ 200 mm) showed that the 12-month primary patency rate was 75.0% for the ≥ 200 mm group and 95.5% for the < 200 mm group. Cox univariate regression analysis did not identify any risk factors affecting primary patency rate and freedom from clinically driven TLR (CD-TLR) at 12 months.Rotarex®S combined with DCB seems safe and provides acceptable 12-month primary patency and TLR rates in femoropopliteal in-stent restenosis. Well-designed comparative or large registry studies are necessary to provide high quality and long-term data on this technique to provide firm conclusions on the efficacy of Rotarex®S and DCB in ISR in the femoropopliteal area.© 2024. The Author(s).